Computing The Binding Free Energy Between TCR And P/MHC Using Weighted Histogram Analysis Method

The TCR recognition of antigenic peptides presented by MHC molecules is high sensitive and specific, which process includes changes in their structure and energy. Exact computation of a macromolecular system’s free energy is facing many difficulties. Generally, The methods of calculating system free energy changes have free energy perturbation method, thermodynamic integration method and thermodynamic integration method. Weighted histogram analysis method combines umbrella sampling with free energy perturbation, and gets the unbiased probability distribution through adding a confinement potential to the sampling windows, so as to obtain a more accurate free energy computation result. This method is universal and it establishes the Bridge between non-equilibrium process and equilibrium free energy.This paper chosen A6T cell and Tax/HLA-A2as acceptor and receptor of protein-protein interaction, computing the free energy changes of the system from binding state to unbinding state. The binding free energy through computing is7.49kCal/mol, having an only error2.9%compared with experimental value of SPR (Surface plasmon resonance).Through analyzing the result data, conclude that there is very important relationship with pulling force constant and pulling rate for the binding free energy accuracy, because when the pulling force is enough large, the molecule will move with constant speed and the dissipation work is small; using the weighted histogram analysis method, selecting the sampling windows is uncertain and strengthening the sampling density is needed.